Prostaglandin pharmaceutical compositions

ABSTRACT

Compounds of the general formula A—X 1 —NO 2 , or their pharmaceutical compositions, wherein A contains a prostaglandin residue, X 1  is a bivalent connecting bridge.

This application is a 371 of PCT/EP98/03645 filed Jun. 17, 1998.

The present invention relates to drugs to be used in male impotence.

In particular it relates to drugs which are used at lower but equallyeffective doses than those commonly used for the treatment of saidtherapy, and combined with fewer side effects, in particular as far asthe absence of hypotension and algogenic activity is concerned.

It is well known in the art that the available therapies for treatingmale impotence are based on different approaches depending on theaetiology.

In the case of impotence due to endocrine causes treatment withtestosterone is used.

In the case of impotence due to vascular alterations, or following fromsome neurological alterations, it is used an intracavernous injection ofvasoactive compounds made by the patient himself before sexualintercourse. This method of administration allows a localpharmacological activity and reduces to a minimum any interference withthe other vascular areas of the body which could lead to severe sideeffects including vasodilation and hypotension. The drugs morefrequently used with said method include the associationpapaverine-phentolamine and Prostaglandin E₁ (PGE₁). This is a usefulapproach from the therapeutic point of view, but it has the disadvantageto presenting side effects. In fact, papaverine induces local fibrosis,prolonged erections and hepatic alterations; Prostaglandin E₁ inducespain in 20% of cases and prolonged erections in 1-2% of cases. PGE₁ isanyhow at the moment the drug most used for this type of therapy.

Besides clinical drug treatments, are well known in the art the use ofprostheses and mechanical devices.

At the present time, the available drugs solve the problem only in alimited number of cases. Research is being made on the basis of varioushypothesis. However, the drugs which have been proposed up to now areless active than prostaglandin-based drugs.

It was felt the need to have drugs as effective in the treatment ofimpotence as least as those based on prostaglandin but withoutpresenting the side effects possessed by said known drugs as describedabove.

It has been surprisingly and unexpectedly found a class of drugs asherein below defined which has an improved activity than prostaglandinand the advantage of being used at lower doses with less side effects,in particular it does not cause any hypotension or algogenic activity.

It is an object of the invention the compounds, or their compositionshaving the general formula

A—X₁—NO₂   (I)

for use as medicaments, in particular as drugs for the treatment ofimpotence, wherein:

A=R(CR_(a)R_(b)O)_(u)(COX)_(t)   (II)

wherein:

t and u are integers and are equal to 0 or 1;

X=O, NH, NR_(1c) wherein R_(1c) is a linear or branched alkyl havingfrom 1 to 10 carbon atoms;

R_(a) and R_(b), equal or different from each other, are H, C₁-C₃ alkyl;

R is a radical having the following formula:

where m₀ is an integer and can have a value of 0 or 1;

where the meaning of the various substituents of formula III is asfollows:

when t=1, u=0 and m₀=1;

R₁=H; an alkyl having from 1 to 6 carbon atoms, preferably from 1 to 3,or a free valence;

R₂=OH; O— such as to form with R₁, when R₁ is a free valence, and withthe carbon atom at position 15, a group C═O,

R₃, R₄, equal or different one from the other, are equal to R₁, or oneof them is a bond O—, and the other is a free valence so that with thecarbon atom C₄ they form a group C═O;

R₅, R₆, equal or different one from the other, are equal to R₁, inparticular when both R₅ and R₃ are each a free valence, R₅ and R₃ form adouble bond between C₅ and C₆;

R₇, R₈, R₉, R₁₀, equal or different one from the other, have the samemeaning of R₁; when R₇ or R₉, and at the same time R₈ or R₁₀ are each afree valence, there is a double bond between C₁₃ and C₁₄;

R₁₁=R₁;

R₁₂=R₁₁ or OH;

R₁₃, R₁₄, R₁₅, R₁₆, equal or different one from the other, are equal toR₁; when R₁₃ or R₁₅, and at the same time R₁₄ or R₁₆, are each a freevalence, there is a double bond between C₁ and C₂;

R₁₇, R₁₈, equal or different one from the other, are equal to R₁;

R₁₉, R₂₀, equal or different one from the other, are equal to R₁; whenR₆ or R₅ is a free valence, and at the same time R₁₉ or R₂₀ is a freevalence, there is a double bond between C₄ and C₅;

R₂₁, R₂₂, R₂₃, R₂₄, equal or different one from the other, are equal toR₁;

R₂₅, R₂₆, equal or different one from the other, are equal to R₁, butboth R₂₅ and R₂₆ cannot be a free valence;

R₂₇ is a linear or whenever possible branched alkyl having from one tosix carbon atoms;

B is equal to the group O═ (a keto group with the carbon atom atposition 9 of the prostaglandin molecule), OH or —O—;

when no aliphatic chain C₇-C₂ is found attached at position 8, in itsplace there is the alkylaromatic residue:

wich is bound to formula (III) (B=—O—) in the following way:

wherein m₁ is an integer from 1 to 6, preferably from 1 to 3;

R_(a) and R_(b), equal or different from each other, are as abovedefined;

when t=0, u=1 and m₀=1 the meanings of the various substituents are asabove defined;

when t=0, u=0 and m₀=0 the meanings of the various substituents are asabove defined and

C₁₆ is bound, optionally by a bridging group —O—, to an aromatic radicalor an alkyl-aril radical, where the aryl can be substituted, preferablywith halogens, preferably with Cl, F; said aryl radical can also containheteroatoms, such as O, N; the alkyl of the alkyl-aril radical is analiphatic chain from 1 to 3 carbon atoms, preferably —CH₂—;

X₁ of formula A—X₁—NO₂ is a bivalent connecting bridge, chosen from thefollowing:

—Y

Y is a linear or whenever possible branched C1-C20 alkylene oxygenterminated, preferably having from 2 to 5 carbon atoms or is a C5-C7cycloalkylene oxygen terminated optionally substituted;

where n₃ is an integer from 0 to 3;

where nf′ is an integer from 1 to 6, preferably from 2 to 4;

where R_(1f)=H, CH₃ and nf is an integer from 1 to 6, preferably from 2to 4.

When in formula (II) t=1 u=0 and in formula (III) m₀=1, the preferredprostaglandin residues R are the following:

when B is O═ (keto group with C₉); R₇, R₈, R₉ and R₁₀ are such as togive a double bond between C₁₃ and C₁₄; R₂ is OH; R₂₇ is CH₃; thesubstituents of the carbon atoms of the C₂-C₇ and C₁₆-C₁₉ aliphaticchains are H; R thus defined is known as the residue of ProstaglandinE₁;

or, by putting in the formula of Prostaglandin E₁ R₂=CH₃ and R₃, R₄, R₅,R₆ such as to give a double bond between C₅ and C₆;

R thus defined it is known as the residue of Arbaprostil;

or, by putting in the formula of Arbaprostil R₇=R₉=R₉=R₁₀=H; R₁ and R₂are such as to form the group C═O with C₁₅; B is OH; R₂₇=C₃H₇, R thusdefined it is known as the residue of Unoprostone;

or, by putting in the formula of Arbaprostil R₁₁=R₁₂=CH₃;

R₁=H, R thus defined it is known as the residue of Trimoprostil;

or, when in the formula of Arbaprostil B is OH; R₁=H; R thus defined itis known as the residue of Prostaglandin F_(2α);

or, when in the formula of Prostaglandin R_(2α) B is O═ (keto group withC₉), R thus defined it is known as the residue of Prostaglandin E₂;

or, when in the formula of Arbaprostil B is OH; R thus defined it isknown as the residue of Carboprost;

or, by putting in the formula of Arbaprostil R₁=H; R₁₇=H; R₁₉=CH₃;R₃=R₄=R₅=R₆=H; R₂₇=C₂H₅; R₁₃=R₁₆=H and R₁₄=R₁₅ being free valences suchas to form a double bond between C2 and C3; R thus defined it is knownas the residue of Limaprost;

or, by putting in the formula of Trimoprostil R₃=R₄=R₅=R₆=H andpositioning the double bond between C₂ and C₃ instead that between C₅and C₆; R thus defined it is known as the residue of Gemeprost;

or, by putting in the formula of Arbaprostil R₁=R₂=H; R₁₂=OH; R₁₁=CH₃;R₃=R₅=R₄=R₆=H; R thus defined it is known as the residue of Misoprost;

or, by putting in the formula of Arbaprostil R₁=H; R₁₈=CH₃; R₂₇=C₂H₅; R₃and R₄ are such that one of them is a free valence and the other is asingle bond with an oxygen atom so so that together with the carbon atomC₆ they form a keto group C═O; R5=R6=H; R thus defined it is known asthe residue of Ornoprostil;

or, as in Arbaprostil, without the C₇-C₂ aliphatic chain and the carbonatoms C₉-C₈ being linked to the group of formula (IV) as shown in (V);R₁=H; R₁₁=CH₃; R₂₁, R₂₂, R₂₃ and R₂₄ being each a free valence so toform a triple bond between C₁₈ and C₁₉; R thus defined it is known asthe residue of Beraprost;

when t=0; u=1 and m₀=1: R_(a)=R_(b)=H and R is the residue ofMisoprostol; R thus defined it is known as the residue of Rioprostil;

when t=1, u=0 and m₀=0:

when R is the residue of Arbaprostil except that R₁=H, R₁₉ or R₂₀ is afree valence or is H, so that between C₄ and C₅ there is a double bond;C₁₆ is linked to a group —O—A_(r) wherein A_(r)=phenyl; R thus definedit is known as the residue of Enprostil;

when R is the residue of Arbaprostil except that B is OH; R₁=H; C₁₆ islinked to a group —CH₂—A_(r) where A_(r) is phenyl; it is defined aradical known as the residue of Latanaprost;

or, when in the formula of Enprostil R₂₀=R₁₉=H; it is defined a radicalknown as the residue of Sulprostone.

The products of the invention are obtained starting from the precursorsin which R is as above defined and containing at least one carboxylicfunction, usually at position 2 of the corresponding formula (III); inthe case of Beraprost the function —COOH is in the residue of formula(IV).

When the precursor has no free function —COOH, reactions to obtain itwhich are well known in the art are performed, for example by reactionof an esther or by oxidation of an alcohol.

The above substances may already exist as such (e.g. Arbaprostil,Prostaglandin E₁, Rioprostil, as described above).

For the precursors described in the literature, which have thecarboxylic function substituted in various ways, in order to perform thesynthesis according to the present invention it is preferable to startfrom the corresponding precursors in the acid form, i.e. bearing e freecarboxylic group.

In particular, as preferred precursors one may mention Prostaglandin E₁,Arbaprostil, Unoprostone, Trimoprostil, Prostaglandin F_(2α),Prostaglandin E₂, Carboprost, Limaprost, Misoprostol, Gemeprost,Latanoprost, Ornoprostil, Beraprost, Enprostil, Rioprostil, Sulpostrone.These substances are prepared according to the methods described in “TheMerck Index”, Ed. 12, herein fully incorporated by reference.

The products of the present invention having the general formula

A—X₁—NO₂

with the connecting bridge X₁ as above defined, are obtainable by usingthe methods of the known art described, for example, in WO 92/01668 andWO 95/30641, herein fully incorporated by reference. In general, theconnection between A and X₁ is of the ester —C(O)O— type or amide—C(O)NH— or —C(O)N(R_(1c))— type, as defined in X of formula (II) above,and can be obtained by using known synthetic routes.

The most direct synthetic route includes reaction of acyl chloridesR—CO—Cl in halogen alcohols of the type HO—Y—Cl, HO—Y—B, HO—Y—I, Y beingX₁ without oxygen in experimental conditions which are part of the knownart.

The reaction products of formula R—CO—O—Y—Cl (Br, I) can also beobtained by reaction of the sodium or potassium salts of said acidsRCOOH with dihalogen derivatives of the general formula YCl₂, YBr₂ orYI₂.

The reaction products are converted into the final products by reactionwith AgNO₃, in acetonitrile, according to the known methods ofliterature.

The general scheme is as follows:

R—CO—Cl+HO—Y—Br→R—CO—O—Y—Br+AgNO₃→A—X₁NO₂

where X₁=YO.

Another general scheme is as follows:

R—CO—ONa+Br₂Y→R—CO—O—Y—Br+AgNO₃→A—X₁NO₂

where X₁=YO.

In the case of amides, the synthetic sequence includes reaction of thesame acyl chlorides RCOCl with aminoalcohols of the general formula:

NH₂—Y—OH, NHR_(1c)—Y—OH

to give amides of the general formula:

R—CO—NH—Y—OH and R—CO—NR_(1c)—Y—OH

according to known methods.

The reaction of these amides with halogenating agents such as, forexample, PCl₅, PBr₃, SOCl₂, and others, leads to halogen derivatives ofthe general formula:

R—CO—NH—Y—Br(Cl) and R—CO—NR_(1c)—Y—Br(Cl).

By reaction with AgNO₃ in acetonitrile according to methods reported inthe literature, are obtained the final products A—X₁—NO₂.

The sequence of the reaction can be schematised as follows:

where YO is X₁.

An alternative route to formation of the esters is reaction of thesodium or potassium salts of the acids with the nitric esters of halogenalcohols of the general formula:

NO₂—O—Y—Cl(Br, l)

to directly give the products of the invention.

The reaction scheme is as follows:

R—CO—ONa+Br—Y—ONO₂→R—CO—O—Y—ONO₂

where YO is X₁.

According to a further process for the preparation of the compounds ofthe invention the acid derivatives RCOOH are reacted with alcoholscontaining in the molecule a group —ONO₂ in the presence of aromaticsulphochlorides, in the presence of bases, such as trialkylamine, whichneutralize the HCl released by the reaction.

Can also be used synthetic routes similar to those described above,where the di-halogen derivative Br₂Y is reacted with —ONa. The reactionproducts are then converted into acetonitrile by reaction with AgNO₃according to the above shown reactions.

The general scheme is shown below

In addition to being used in the treatment of male impotence asexplained at the beginning, the product of the invention can also beused in the known therapeutic applications of drugs containingprostaglandins as the active ingredient, such as in the treatment ofcerebrovascular and cardiovascular disorders, glaucoma, peptic ulcer andas abortifacients.

In particular, the derivatives of Prostaglandin E₁ are preferred.

Following treatment of experimental animals with the new substances, nohypotension reactions nor the algogenic activity possessed byprostaglandins were observed. In fact, differently from PGE₁, the newderivatives of the invention were inactive in pain-induction tests.

The examples below explain the purpose of the invention and should notbe understood as a limitation of same.

EXAMPLE 1 Synthesis of 2-nitroxyethyl ester of prostaglandin E₁

19.1 mg (0,0539 mmoles) of PGE₁ was dissolved in 0.7 ml of absoluteacetone in a 5-ml flask. 11,5 mg (0,0604 mmol) ofp-toluenesulphochloride, 12 mg (0,01188 mmoles) of triethylamine and 8mg (0,9748 mmoles) of 2-nitroethanol were then added to the solution.The flask was closed and the reaction mixture was stirred for 22 hoursat room temperature. At the end the solvent was evaporated off undervacuum, the residue was treated with 3 ml of water and the mixture wasextracted with ethyl acetate three times using 7 ml each time.

The pooled organic extracts were washed with 1 ml of water and then 1,5ml of a saturated NaCl solution. After drying over sodium sulphate, theywere evaporated off to dryness under vacuum.

The oily residue which was obtained was dissolved in the lowest amountof dichloromethane and chromatographed using a small column packed with4 g of silica gel (Silica gel 60 Å, 230-400 mesh). Dichloromethane wasused as the initial eluant followed by a mixture of dichloromethane andethyl acetate which was gradually enriched with the second component upto eluting with pure ethyl acetate. The column was then eluted with amixture of ethylacetate/methanol, gradually enriched with methanol, upto using the pure alcohol. The fractions were analysed by TLC on silicagel (Silica Gel 60 F₂₅₄), using the eluting mixtureethyl-acetate/acetic-acid 20/0,5. The test tubes containing the reactionproduct were those containing the eluates with pure ethyl acetate. Saideluates were joined together and the solvent was evaporated off toobtain 6 mg of a colourless oil (yield 25%) having an Rf in the aboveTLC elution system equal to 0,38. The ¹H NMR spectrum (CD₃OD) shows allsignals corresponding to PGE₁ (ppm): 5 6 (m, 2H), 4-4,2(m,2H),2,6-2,8(quartet, 1H), 2,0-2,4(m), 1,2-1,8(m). Furthermore, twomultiplets centred at δ=4,75 (2H) and δ=4,4(2H) respectively,corresponding to the two methylene groups of 2-nitroethanol esterifiedwith the carboxylic group of PGE₁, were observed.

I.R. spectrum: 3382 cm⁻¹ (OH), 2858-2930 cm⁻¹ (—CH—, —CH₂, —CH₃—), 1774cm⁻¹ (C=O ester), 1773 cm⁻¹ (group C=O in a five atom ring), 1634 and1280 cm⁻¹ (—O—NO₂). 12,4 mg (65% of the starting amount) of unreactedPGE₁ was recovered from the chromatographic fractions eluted with theethylacetate/methanol mixture.

Pharmacological tests

In the pharmacological tests, the products were administered to animalsby local injection in a physiological solution.

The control groups were treated with a physiological solution.

Prostaglandin E₁, sodium nitroprusside and SIN-1, chemically defined as3-(4-morpholinyl)sydnone imine, which is the active metabolite ofmolsidomine, were used as reference products.

EXAMPLE 2 Relaxing effect in vitro on isolated human cavernosus arteryand cavernosus corpus

The method described by Hempelmann R. G. et al., European Journal ofPharmacology, 1995, 276, 277-280, was followed using erectile tissuesfrom patients subjected to surgery.

The cavernosus arteries were isolated and cleaned of the surroundingconnective tissue. Segments about 2-mm long were obtained and mounted ina myograph.

After building a diameter/tension curve, the artery segments wereadjusted to a diameter corresponding to 90% of that reached in thepresence of a trasluminal pressure of 100 mmHg. After a stabilisationperiod of about 60 minutes, a contraction was induced by the addition of3×10⁻⁶M adrenaline. After 15 minutes, the test compounds wereadministered at a concentration of 10⁻⁶M and the per-cent relaxationinduced by the administration of the test product was recorded for each.The results are shown in Table 1.

Another set of experiments was conducted according to the samemethodology, using isolated strips of cavernous tissue about 3×3×5 mm insize suspended isometrically, with application of a 5-10 mN tension inbaths for isolated organs. The results are shown in Table 2.

In both experimental models an inhibitory effect of theadrenalin-induced contraction following either treatment with PGE₁ oradministration of the nitric-acid-donor SIN-1 was found. The PGE₁derivative according to the present invention is shown in the tables bythe abbreviation NO-PGE₁.

This compound showed an effect superior to both native prostaglandin andSIN-1.

TABLE 1 Inhibitory effect of some derivatives on isolated humancavernosus artery pre-contracted with 3 × 10⁻⁶ M adrenalin (for eachtreatment group n = 5 replications) inhibition of contraction Treatment(%) 10⁻⁶M PGE₁ 19 ± 4 10⁻⁶M SIN-1 36 ± 7 10⁻⁶M NO-PGE₁ 41 ± 9

TABLE 2 Inhibitory effect of some derivatives on isolated humancavernosus tissue pre-contracted with 3 × 10⁻⁶ M adrenaline (for eachtreatment group n = 4) inhibition of contraction Treatment (%) 10⁻⁶MPGE₁ 52 ± 5 3 × 10⁻⁶M SIN-1 41 ± 6 10⁻⁶M NO-PGE₁ 71 ± 6

EXAMPLE 3 Evaluation of induced erection activity and of hypotensiveeffect in rats

The method described by Pineiro et al., European Urology 1993, 24,492-499, was used. Male rats weighing about 350 g (5 animals/group) wereanaesthetised with urethane and maintained at a temperature of 37° C.throughout the test. The cavernosus corpuses were exteriorized byperineal section. The right cavernosus corpus was connected to apressure transducer using a heparinised catheter and the left one wasconnected using a PE-10 plastic tube to a syringe by which the productswere administered.

The right carotide artery was cannulated and connected to a pressuretransducer to measure the systemic blood pressure. The products wereadministered intracavernously at a volume of 0.03 ml at a 10⁻³Mconcentration and the intracavernous pressure and systemic bloodpressure were monitored. The results given in Table 3 show that PGE₁ wasslightly active in this model, while sodium nitroprusside induced aremarkable erection activity. Both derivatives caused a drop in systemicblood pressure, which was particularly marked in the case ofnitroprusside. NO-PGE₁ showed an effect superior to both PGE₁ and sodiumnitroprusside on intracavernous pressure, while causing a nonsignificant drop in systemic blood pressure, which was comparable tothat of starting Prostaglandin, and was significantly lower than that ofnitroprusside.

As a result, the products of the invention have been shown to possess apharmacodynamic profile which is more favourable compared to thereference compounds.

TABLE 3 Effect of intracavernosus treatment of various derivatives onintracavernosus pressure (P) and systematic blood pressure (P) inanaesthetised rats (n = 4) Increase in Drop in intracavernous systemic PTreatment P (cm H₂O) 10⁻³M sodium nitroprusside 27 ± 3,7   51 ± 7,810⁻³M PGE₁ 0,7 ± 0,4  18,2 ± 2,2 10⁻³M NO-PGE₁ 36 ± 1,4  9,1 ± 3,1

EXAMPLE 4 Inducted erection activity in rabbits

The method described by Stackl W. et al., Urological Research 1988,455-458, was used. Male rabbits weighing about 2 Kg (n. 6 animals/group)were injected 1 ml of physiological solution containing 20 μg of thetest products into the right cavernosus corpus. During the injection,complete penis protrusion was observed, which was considered as 100%erection.

After injection, at pre-determined time intervals (0,5, 1,2 and 3hours), the animals were observed for the presence of erection andevaluation of the relevant per-cent extent according to the followingscheme:

0%=penis not visible

25%=glans visible

50%=penis protrusion equal to about half the complete lenght

75%=penis protrusion not complete, but greater than half the lenght

100%=complete penis protrusion

The results are given in Table 4 and show that the compound of theinvention had a superior activity to that of the reference compound.

TABLE 4 Average per-cent values of extent of erection observed atdifferent time intervals after intracavernosus administration of PGE₁,derivatives in rabbits 30 Treatement n minutes 1 hour 2 hours 3 hoursControls 4 6  0% 0% 0% PGB₁ 20 μg 6 13% 4% 0% NO-PGE₁ 6 92% 79%  67% 46%  20 μg

EXAMPLE 5 Effect on painful response of the compound of the invention inrats

The conventional method of Randall-Selitto modified as described inDuarte I. D. G. et al., European Journal of Pharmacology, 1990, 186,289-293, was used to determine the potential activity on painfulresponse of the compound. The test includes the application of a steady20-mmHg pressure to a back paw of rats. Pressure application wasdiscontinued when the animals appeared to react and the response latencytime, which was the parameter used to evaluate the analgesic orhyperalgesic effect of the test product, was recorded. Immediatelyafter, the product was administered by the intradermal route in thesubplantar area (administration volume 2,5 μl containing 0,1 μg of thetest product). The test was repeated 3 hours later.

The results given in Table 5 show that PGE₁ reduced the latency time,i.e. acted as a hyperalgesic agent. Sodium nitroprusside caused a slightnonsignificant increase in latency time. NO-PGE₁ was inactive, thusshowing that the NO group in the PGE₁ molecule reduced the hyperalgesicproperty. In the table, the column identified by an “n” shows the numberof animals used for each treatment.

TABLE 5 Effect of the compound of invention and reference substances onmodified Randal-Selitto test reaction time Product (μg/paw) n change(seconds) PGE₁ (0,1) 8 −17 ± 2 Sodium 8  +4 ± 2 nitroprusside (5)NO-PGE₁ (0,1) 10 0

The derivatives were active in various tests useful to evaluate thepotential pharmacological induced-erection activity versus referencecompounds.

Unlike sodium nitroprusside, the invention compounds induced nohypotension at the pharmacologically active doses in the experimentalimpotency models.

The invention compounds showed no pain effects which could be foundafter the administration of PGE₁ in experimental tests in rats.

What is claimed is:
 1. Compounds of the formula A—X₁—NO₂   (I) wherein Ais R(CR_(a)R_(b)O)_(u)(COX)_(t)   (II) wherein t and u are integers andare equal to 0 or 1; X═O, NH, NR_(1c) wherein R_(1c) is a linear orbranched alkyl having form 1 to 10 carbon atoms; R_(a) and R_(b) areequal to or different from each other and are H, or a C₁-C₃ alkylradical and R is a radical having the following formula:

wherein m₀ is an integer having a value of 0 or 1; and when t=1, u=0 andm₀=1: R₁=H; an alkyl having from 1 to 6 carbon atoms or a free valance;R₂=OH, O— such as to form with R₁ when R₁ is a free valance, and withthe carbon atom at position 15 a C═O group; R₃ and R₄ are equal to ordifferent from one another and are equal to R₁ or one of them is a bondO—, and the other is a free valance so that with the carbon atom C₆ theyform a C═O group; R₅ and R₆ are equal to or different from one another,and are equal to R₁ when both R₅ and R₃ are each a free valence, R₅ andR₃ form a double bond between C₅ and C₆; R₇, R₈, R₉, and R₁₀ are equalto or different from each other, and have the same meaning as R₁; whenR₇ or R₉, and at the same time R₈ or R₁₀ are each a free valence, thereis a double bond between C₁₃ and C₁₄; R₁₁=R₁; R₁₂=R₁₁ or OH; R₁₃, R₁₄,R₁₅, and R₁₆ are equal to or different from each other, and are equal toR₁; when R₁₃ or R₁₅, and at the same time R₁₄ or R₁₆, are each a freevalence, there is a double bond between C₃ and C₂; R₁₇ and R₁₈ are equalto or different from each other and are equal to R₁; R₁₉ and R₂₀ areequal to or different from each other and are equal to R₁; when R₆ or R₅is a free valence, and R₁₉ or R₂₀ is a free valence, there is a doublebond between C₄ and C₅; R₂₁, R₂₂, R₂₃, and R₂₄ are equal to or differentfrom each other and are equal to R₁; R₂₅ and R₂₆ are equal to ordifferent from each other and are equal to R₁, but both R₂₅ and R₂₆cannot be a free valence, R₂₇ is a linear or branched alkyl having oneto six carbon atoms; B is equal to the group O— (a keto group with thecarbon atom at position 9 of the prostaglandin molecule) or is OH or—O—; when no aliphatic chain C₇-C₂ is at position 8, there is in itsplace an alkylaromatic residue:

which is bound to formula (III) (B=—O—) in the following way:

wherein m₁ is an integer from 1 to 6, R_(a) and R_(b) are equal to ordifferent from each other, and are as defined above, when t=0, u=1, andm₀=1 the meanings of the various substituents are as defined above, whent=1, u=0, and m₀=0 the meanings of the various substituents are asdefined above and C₁₆ is bound, optionally by a bridging group —O—, toan aromatic radical or an alkyl-aryl radical, where the aryl can besubstituted, said aryl radical can also contain heteroatoms, such as Oor N; the alkyl of the alkyl-aryl radical is an aliphatic chain from 1to 3 carbon atoms; X₁ of formula A—X₁—NO₂ is a bivalent connectingbridge, chosen from the following: —Y where Y is a linear or wheneverpossible branched C₁-C₂₀ alkylene oxygen terminated, or is a C₅-C₇cycloalkylene oxygen terminated optionally substituted;

where n₃ is an integer from 0 to 3;

where nf′ is an integer from 1 to 6; and

where R_(1f)=H or CH₃, and nf is an integer from 1 to
 6. 2. Compoundsaccording to claim 1 wherein the prostaglandin residues R are thefollowing: when in formula (II) t=1 u=0 and in formula (III) m₀=1: B isO═ (keto group with C₉); R₇, R₈, R₉ and R₁₀ are such as to given adouble bond between C₁₃ and C₁₄; R₂ is OH; R₂₇ is CH₃; the substituentsof the carbon atoms of the C₂-C₇ and C₁₆-C₁₉ aliphatic chains are H; Rthus defined is known as the residue of Prostaglandin E₁; or, by puttingin the formula of Prostaglandin E₁, R₁=CH₃ and R₃, R₄, R₅, R₆ such as togive a double bond between C₅ and C₆; R thus defined is known as theresidue of Arbaprostil; or, by putting in the formula of ArbaprostilR₇=R₈=R₉=R₁₀=H; R₁ and R₂ are such as to form the group C═O with C₁₅; Bis OH; R₂₇=C₃H₇; R thus defined is known as the residue of Unoprostone;or, by putting in the formula of Arbaprostil R₁₁=R₁₂=CH₃, R₁=H, R thusdefined s known as the residue of Trimoprostil; or, when in the formulaof Arbaprostil B is OH; R₁=H; R thus defined is known as the residue ofProstaglandin F_(2α); or, when in the formula of Prostaglandin F_(2α) Bis O═ (keto group with C₉); R thus defined is known as the residue ofProstaglandin R₂; or, when in the formula of Arbaprostil B is OH; R thusdefined is known as the residue of Carboprost; or, by putting in theformula of Arbaprostil R₁=H; R₁₇=H; R₁₉=CH₃; R₃=R₄=R₅=R₆=H; R₂₇=C₂H₅;R₁₃=R₁₆=H and R₁₄=R₁₅ being free valences such as to form a double bondbetween C₂ and C₃; R thus defined is known as the residue of Limaprost;or, by putting in the formula of Trimoprostil R₃=R₄=R₅=R₆=H, andpositioning the double bond between C₂ and C₃ instead that between C₅and C₆; R thus defined is known as the residue of Gemeprost; or, byputting in the formula of Arbaprostil R₁=R₂=H; R₁₂=OH; R₁₁=CH₃,R₃=R₅=R₄=R₆=H; R thus defined is known as the residue of Misoprost; or,by putting in the formula of Arbaprostil R₁=H; R₁₈=CH₃; R₂₇=C₂H₅; R₃ andR₄ are such that one of them is a free valence and the other is a singlebond with an oxygen atom so that together with the carbon atom C₆ form aketo group C═O; R5=R6=H, R thus defined is known as the residue ofOrnoprostil; or, as in Arbaprostil, without the C₇-C₂ aliphatic chainand the carbon atoms C₉-C₈ linked to the group of formula (IV) as shownin (V); R₁=H; R₁₁=CH₃; R₂₁, R₂₂, R₂₃, R₂₄ being each a free valence toform a triple bond between C₁₈ and C₁₉; R thus defined is known as theresidue of Beraprost; when t=0; u=1 and m₀=1: R_(a)=R_(b)=H and R is theresidue of Misoprostol, R thus defined is known as the residue ofRioprostil, when t=1, u=0 and m₀=0: when R is the residue of Arbaprostilexcept that R₁=H; R₁₉ or R₂₀ is a free valence or H, so that between C₄and C₅ there is a double bond; C₁₆ is linked to a group —O—A_(r) whereinA_(r)=phenyl; R thus defined is known as the residue of Enprostil; whenR is the residue of Arbaprostil except that B is OH; R₁=H; C₁₆ is linkedto a group —CH₂—A_(r) where A_(r) is phenyl; it is defined a radicalknown as the residue of Latanaprost; when in the formula of EnprostilR₂₀=R₁₉=H; it is defined a radical known as the residue of Sulprostone.3. A compound according to claim 1 where R is the residue ofProstaglandin E₁.
 4. A method for treating cerebrovascular andcardiovascular disorders, glaucoma, and peptic ulcer disorders, and amethod for inducing abortion, comprising administering to a patient aneffective amount of a compound of claim
 1. 5. Pharmaceuticalcompositions containing as the active ingredient compounds of claim 1and a pharmaceutically acceptable carrier.
 6. A method for treatingimpotence comprising administering to a patient an effective amount of acompound of the formula: A—X₁—X—X₁—NO₂   (I) wherein A isR(CR_(a)R_(b)O)_(u)(COX)_(t)   (II) wherein t and u are integers and areequal to 0 or 1; X═O, NH, NR_(1c) wherein R_(1c) is a linear or branchedalkyl having form 1 to 10 carbon atoms; R_(a) and R_(b) are equal to ordifferent from each other and are H, or a C₁-C₃ alkyl radical and R is aradical having the following formula:

wherein m₀ is an integer having a value of 0 or 1; and when t=1, u=0 andm₀=1: R₁=H; an alkyl having from 1 to 6 carbon atoms or a free valance;R₂=OH, O— such as to form with R₁ when R₁ is a free valance, and withthe carbon atom at position 15 a C═O group; R₃ and R₄ are equal to ordifferent from one another and are equal to R₁ or one of them is a bondO—, and the other is a free valance so that with the carbon atom C₆ theyform a C═O group; R₅ and R₆ are equal to or different from one another,and are equal to R₁ when both R₅ and R₃ are each a free valence, R₅ andR₃ form a double bond between C₅ and C₆; R₇, R₈, R₉, and R₁₀ are equalto or different from each other, and have the same meaning as R₁; whenR₇ or R₉, and at the same time R₈ or R₁₀ are each a free valence, thereis a double bond between C₁₃ and C₁₄; R₁₁=R₁; R₁₂=R₁₁ or OH; R₁₃, R₁₄,R₁₅, and R₁₆ are equal to or different from each other, and are equal toR₁; when R₁₃ or R₁₅, and at the same time R₁₄ or R₁₆, are each a freevalence, there is a double bond between C₃ and C₂; R₁₇ and R₁₈ are equalto or different from each other and are equal to R₁; R₁₉ and R₂₀ areequal to or different from each other and are equal to R₁; when R₆ or R₅is a free valence, and R₁₉ or R₂₀ is a free valence, there is a doublebond between C₄ and C₅; R₂₁, R₂₂, R₂₃, and R₂₄ are equal to or differentfrom each other and are equal to R₁; R₂₅ and R₂₆ are equal to ordifferent from each other and are equal to R₁, but both R₂₅ and R₂₆cannot be a free valence, R₂₇ is a linear or branched alkyl having oneto six carbon atoms; B is equal to the group O═ (a keto group with thecarbon atom at position 9 of the prostaglandin molecule) or is OH or—O—; when no aliphatic chain C₇-C₂ is at position 8, there is in itsplace an alkylaromatic residue:

which is bound to formula III (B=—O—) in the following way:

wherein m₁ is an integer from 1 to 6, R_(a) and R_(b), are equal to ordifferent from each other, and are as defined above, when t=0, u=1, andm₀=1 the meanings of the various substituents are as defined above, whent=1, u=0, and m₀=0 the meanings of the various substituents are asdefined above and C₁₆ is bound, optionally by a bridging group —O—, toan aromatic radical or an alkyl-aryl radical, where the aryl can besubstituted, said aryl radical can also contain heteroatoms, such as Oor N; the alkyl of the alkyl-aryl radical is an aliphatic chain from 1to 3 carbon atoms; X₁ of formula A—X₁—NO₂ is a bivalent connectingbridge, chosen from the following: —Y where Y is a linear or wheneverpossible branched C₁-C₂₀ alkylene oxygen terminated, or is a C₅-C₇cycloalkylene oxygen terminated optionally substituted;

where n₃ is an integer from 0 to 3;

where nf′ is an integer from 1 to 6; and

where R_(1f)=H or CH₃, and nf is an integer from 1 to 6.